Vol. 289, Issue 3, 1539-1544, June 1999

The Effects of Morphine-Induced Increases in Extracellular Acetylcholine Levels in the Rostral Ventrolateral Medulla of Rat

Kyoji Taguchi, Masatoshi Kato, Jun Kikuta, Kenji Abe, Toshiyuki Chikuma, Iku Utsunomiya and Tadashi Miyatake

Department of Neuroscience (K.T., M.K., J.K., K.A., I.U., T.M.) and Pharmaceutical Analysis Chemistry (T.C.), Showa College of Pharmaceutical Sciences, Higashitamagawagakuen, Machida, Tokyo, Japan

The present study examined the role of the rostral ventrolateral medulla (RVLM) in the modulation of acetylcholine (ACh) release by morphine. We examined the effect of morphine on the release of ACh in the RVLM of freely moving rats using the in vivo microdialysis method. The basal level of ACh was 303.0 ± 28.2 fmol/20 µl/15 min in the presence of neostigmine (10 µM). Morphine at a low dose of 5 mg/kg (i.p.) increased ACh release by the RVLM by 42.4%. A higher morphine dose (10 mg/kg i.p.) significantly increased the release of ACh by 75.4%, with a maximal effect (86.4%) at 75 min. This enhancement following i.p. administration of morphine was reversed by naloxone (1 mg/kg i.p.). Addition of morphine (10⁴ M) to the perfusion medium increased the ACh release by 85.8% of the predrug values. The increased ACh release induced by local application of morphine was reversed by pretreatment with naloxone (1 mg/kg i.p.). The antinociceptive effect of locally applied morphine into the RVLM was assessed using the hot-plate test and tail immersion test in unanesthetized rats. Local application of morphine (10⁴ M) via a microdialysis probe induced an increase in both tail withdrawal and hot-plate response. These findings suggest that morphine seems to exert a direct stimulatory effect on ACh release by the RVLM and that morphine-induced nociception is, in part, activated by the release of ACh in freely moving rats.